Neuromelanin

Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is expressed in large quantities in catecholaminergic cells of the substantia nigra pars compacta and locus coeruleus, giving dark color to the structures.

Neuromelanin is found in higher concentrations among humans than in other primates. Neuromelanin-containing neurons in the substantia nigra undergo neurodegeneration during Parkinson's disease. Neuromelanin concentration increases with age, suggesting a role in neuroprotection (neuromelanin can chelate metals and xenobiotics⁺) or senescence.

Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH) and aromatic acid decarboxylase (AADC). Alternatively, synaptic vesicles and endosomes accumulate cytosolic dopamine (via vesicular monoamine transporter 2 (VMAT2) and transport it to where it is metabolized by monoamine oxidase. Excess dopamine and DOPA molecules are oxidized by iron catalysis into quinones and semiquinones which are then phagocytosed and are stored as neuromelanin.

Motor symptoms of Parkinson's disease are caused by cell death in the substantia nigra, which may be partly due to oxidative stress. This oxidation may be relieved by neuromelanin. Patients with Parkinson's disease had 50% the amount of neuromelanin in the substantia nigra as compared to similar patients of their same age, but without Parkinson's. The death of neuromelanin-containing neurons in the substantia nigra, pars compacta, and locus coeruleus have been linked to Parkinson's disease and also have been visualized in vivo with neuromelanin MRI. Neuromelanin has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.

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